Differential regulation of IL-4Ralpha expression by antigen versus cytokine stimulation characterizes Th2 progression in vivo

J Immunol. 2010 Jan 15;184(2):615-23. doi: 10.4049/jimmunol.0902408. Epub 2009 Dec 16.


IL-4 promotes Th2 differentiation and provides immunity to helminth infections but is also associated with allergy and asthma. This suggests that precise adjustment of IL-4 responsiveness is needed to correctly balance immune responses. The IL-4Ralpha chain is an essential component of the IL-4 receptor and signals via STAT6. In this study, we show that infection with a helminth pathogen elicited broad upregulation of IL-4Ralpha on bystander CD4+ T cells in the draining lymph node, while simultaneously resulting in the loss of IL-4Ralpha expression on activated Th2 cells. IL-4Ralpha upregulation was restricted to the reactive lymph node, occurred within 4 d of infection, and was driven by an IL-4- and STAT6-dependent mechanism. Mice heterozygous for Stat6 exhibited reduced IL-4Ralpha upregulation and a correspondingly attenuated Th2 response. Indeed, the enhanced IL-4Ralpha upregulation in BALB/c mice, compared with that in C57BL6 mice, predicted their stronger Th2 response. The selective downregulation of IL-4Ralpha on highly activated Th cells was triggered by antigenic stimulation, was accompanied by loss of IL-7Ralpha, and rendered the cells unresponsive to IL-4. Together these data reveal a tightly controlled program of changing IL-4 responsiveness that characterizes the initiation, amplification, and restriction of a Th2 response in vivo.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens / immunology*
  • Bystander Effect
  • Cell Differentiation / immunology
  • Cytokines / immunology*
  • Gene Expression Regulation / immunology*
  • Helminths / immunology
  • Interleukin-4 / immunology*
  • Interleukin-4 Receptor alpha Subunit / genetics*
  • Interleukin-4 Receptor alpha Subunit / immunology
  • Lymph Nodes / immunology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • STAT6 Transcription Factor / immunology
  • Th2 Cells / cytology
  • Th2 Cells / immunology*


  • Antigens
  • Cytokines
  • Interleukin-4 Receptor alpha Subunit
  • STAT6 Transcription Factor
  • Stat6 protein, mouse
  • Interleukin-4